RESEARCH Open Access

The neuropsychological phenotype ofChediak-Higashi diseaseTalia N. Shirazi1, Joseph Snow1*, Lillian Ham1, Greta B. Raglan1, Edythe A. Wiggs2, Angela C. Summers1,Camilo Toro2 and Wendy J. Introne2

Abstract

Background/objectives: Chediak-Higashi Disease (CHD) is a rare autosomal disorder, purported to have cognitiveand neurological impairments. Prior descriptions of cognitive impairment, however, are solely based on subjective,unstructured observations rather than on formal neuropsychological measures.

Methods: Four pediatric and 14 adult patients with diagnostically confirmed CHD were administered aneuropsychological battery assessing memory, attention, processing speed, psychomotor speed, language fluency,executive function, and general intelligence. Nine of the adult patients received follow-up evaluations to elucidatethe longitudinal progression or stability of cognition over time.

Results: Pediatric CHD patients performed within the average range. Adult patients, however, performed belowaverage on nearly all measures administered, and endorsed subjective reports of learning difficulties and pooracademic performance in childhood. In particular, patients struggled with memory and psychomotor speed tasks,with 75% or more of patients scoring in the bottom 2.3 percentile in these two domains. No significant declines incognition were observed among the patients who completed follow-up evaluations (M = 39.90, SD = 8.03 monthsbetween visits). Exploratory analyses suggested that adult patients who had classic CHD and previously receivedbone marrow transplants (BMTs; n = 3) exhibited moderately greater cognitive impairment than adult patients whohad atypical CHD and had not received BMTs (n = 10).

Conclusions: Adult patients with CHD uniformly exhibit deficits in multiple domains, but in psychomotor speedand memory, in particular. Based on their neuropsychological profile, their ability to hold jobs and succeed inschool may require support and special accommodations. The source of cognitive deficits is probably multifactorialincluding central nervous system involvement in CHD, and, for those transplanted, BMT-related side effects andcomplications. Absence of cognitive decline at three-year follow-up is encouraging but does not excludeprogression at a slower time-scale. Future work should elucidate the possible effects and timing of BMT oncognition, as well as the mechanisms driving neuropsychological impairment in CHD.

Keywords: Chediak-Higashi disease, Intellectual disability, Neuropsychology, Bone marrow transplant

BackgroundChediak-Higashi Disease (CHD) is an autosomal reces-sive disorder caused by mutations in the LYST gene, withfewer than 500 reported cases worldwide [1]. Centralclinical features include immunodeficiency, partial albin-ism, neutropenia, mild bleeding tendency, and neurode-velopmental disorders during childhood [2]. Without

bone marrow transplantation, up to 85% of patients withCHD develop hemophagocytic lymphohistiocytosis(HLH), or the “accelerated” phase of the disease, inchildhood, which can result in organ failure and death.Hematopoietic stem cell transplantation has been shownto be an effective treatment correcting the hematologicand immunologic aspects of the disease and reducingthe likelihood of the accelerated phase, particularly whenconducted prior to the onset of accelerated symptoms[3, 4]. Without bone marrow transplant, fewer than 10%of CHD patients survive past childhood [5]. A subset of

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: JosephSnow@mail.nih.gov1National Institute of Mental Health, 10 Center Drive, MSC 1274, Bethesda,MD 20892, USAFull list of author information is available at the end of the article

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 https://doi.org/10.1186/s13023-019-1049-x

patients with a diagnosis of CHD confirmed by molecu-lar genotyping, exhibit attenuated clinical features ofCHD (‘atypical’ CHD) and are able to survive into adult-hood without hematopoietic cell transplantation andwithout signs of HLH.In spite of the progress made towards improving survival

and treating the central features of CHD, neurologic deteri-oration has been noted in adult CHD patients including per-ipheral neuropathy, motor weakness, ataxia andParkinsonism [6–12]. Instances of severe neuronal degener-ation in the cortex, basal ganglia, and brainstem have alsobeen reported [8, 10, 13]. It is unknown whether this second-ary neurological impairment is accompanied by impairmentsand declines in cognition and everyday functioning.Though case reports of CHD often include discussion of

impairments in cognition and everyday functioning [5, 9,14–16], the majority do not base such classifications on for-mal neuropsychological testing. Rather, researchers drawinferences about neuropsychological function on the basisof reported school performance or ability to work. Of thefew published case reports of CHD patients where formalneuropsychological tests were administered, all have re-ported intellectual disability based on IQ [17, 18], but donot provide data on the integrity of individual neuropsycho-logical domains. Observations of intellectual disability havebeen made in both children and adults with CHD.Later-life declines in neuropsychological function have

been noted in several [5, 10], though not all [6], case studiesof CHD patients. The relatively small sample sizes in suchstudies combined with the lack of longitudinal neuro-psychological data make such studies hard to generalize.Additional factors such as consanguineous parentage andwhether a patient received a bone marrow transplant mayaffect cognition [19–22], further contributing to the inabil-ity to generalize results from case reports to other patients.The presence of such factors also hinders the ability to iso-late the impact of CHD itself on cognition [8, 23].It is clear that the cognitive presentation of adults with

CHD is variable, but no study has systematically assessedthe neuropsychological phenotype of CHD patients.Additionally, the lack of longitudinal information aboutperformance on formal cognitive measures means littleinformation is available on neuropsychological progres-sion in CHS patients. Finally, as studies have previouslyreported global measures of neuropsychological func-tion, the pattern of neuropsychological function acrossvarious cognitive domains remains unknown. The pur-poses of this study are to describe current functioning ina relatively large cohort of CHD patients as measured bytraditional neuropsychological measures, to examine theprogression of symptoms over time in those cases inwhich follow-up data allows, to determine the effect ofage on functioning in CHD patients cross-sectionally bycomparing adult and pediatric patients, and to evaluate

the relationship between cognitive functioning and clin-ical markers of syndrome severity.

MethodRecruitmentPatients were recruited between 2005 and 2016 toparticipate in a National Human Genome ResearchInstitute Institutional Review Board-approved study onChediak-Higashi Disease (NCT identifier NCT00005917).Patients were also referred to the study by the CHD pa-tient support group, the internet (Clinicaltrials.gov), andthrough national meetings. All patients enrolled in thestudy were confirmed to have CHD by observing giant in-clusions within leucocytes and molecular and cell biologicstudies. Informed consent was obtained from all patients.See Table 1 for demographic information.

Neuropsychological proceduresFormal neuropsychological assessments were conductedat the National Institutes of Health (NIH) by licensedclinical neuropsychologists (JS and EAW), psychologists,or by trained psychometrists. Pediatric patients were ad-ministered a measure of general intelligence and parentsfilled out a self-report form on behavioral and emotionalfunctioning (see Table 2). Adult patients were adminis-tered a comprehensive neuropsychological battery asses-sing memory, attention, processing speed, psychomotorspeed, language fluency, executive function, and generalintelligence (see Table 3). When time permitted, patientsand informants also filled out validated self-report mea-sures of executive function. In addition, some patientscompleted self-report measures of depression and anx-iety in order to assess mood. In the event that thesemeasures were not completed at the initial assessment(i.e., informant did not return the form or the form wasnot administered), we obtained this information from asubsequent visit. We provide results for these behaviorand mood measures gathered at baseline or at subse-quent visits in Table 4. As not all tests were adminis-tered for all participants, we report the number ofpatients who completed each test along with its descrip-tive statistics. Descriptive statistics are reported asT-scores, which have a mean of 50 and standard devi-ation (SD) of 10. Variables based on tests conducted atthe NIH that are typically reported using other statistics(e.g., IQ scores typically are reported as standard scoreshave a mean of 100 and SD of 15) were linearly trans-formed to T-scores based on the normal distribution.Lower T-scores indicate poorer performance with theexception of FrSBe and CBCL scores (informant reportsfor adults and children, respectively) where higher scoresindicate greater dysfunction. T-scores on the Conners’Continuous Performance Test-II were reverse-scored sothat lower T-score reflects greater impairment. As CHD

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 2 of 13

Table

1Adu

ltCHDpatient

demog

raph

ics

Patient

IDAge

atinitialvisit

LYST

variants

CHDdiagno

sis

Transplant

(age

attransplant)

Psycho

trop

icMed

ications

CHD-19*

17p.R1104X

p.G3408R

Atypical

No

Non

e

CHD-27

21Unkno

wn

Unkno

wn

Classic

Yes(3

years)

Non

e

CHD-26

21p.R503X

p.G3309S

Atypical

No

Non

e

CHD-18*

22p.R1104X

p.G3408R

Atypical

No

Non

e

CHD-35

22p.E489DfsX7

8p.E489DfsX7

8Classic

Yes(6

mon

ths)

Non

e

CHD-24†

23p.A1454D

p.Y1687X

Atypical

No

Non

e

CHD-23†

26p.A1454D

p.Y1687X

Atypical

No

Non

e

CHD-17

28p.L1425YfsX1

p.E2810K

Atypical

No

Non

e

CHD-5

28p.V2651F

Unkno

wn

Atypical

No

Lithium,Lam

ictal,Zo

loft

(offLithium

bysecond

visit)

CHD-30

29Unkno

wn

Unkno

wn

Classic

Yes(10years)

Non

e

CHD-20

31p.R1104X

p.R1104X

Classic

No

Non

e

CHD-31#

33p.N3276_T3277de

lp.N3276_T3277de

lAtypical

No

Non

e

CHD-33#

38p.N3276_T3277de

lp.N3276_T3277de

lAtypical

No

Non

e

CHD-32#

43p.N3276_T3277de

lp.N3276_T3277de

lAtypical

No

Non

e

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 3 of 13

Table

1Adu

ltCHDpatient

demog

raph

ics(Con

tinued)

Patient

IDAvailablePriorEvaluatio

nResults

PriorNeuropsycho

logicalD

iagn

oses

Assistancein

scho

olInitialVisitOccup

ation

Current

Occup

ation

CHD-19*

Est.FSIQ

=78

(at9yrs.7mos)

Diagn

osed

ADHD

IEPgrades

2–7;special

educationcourses

Stud

ent

Une

mployed

CHD-27

Non

eDiagn

osed

learning

disability

IEPgrades

K-12;spe

cial

educationcourses;repe

ated

kind

ergarten

Com

mun

ityCollege

stud

ent

Day

care

provider

CHD-26

Non

eDiagn

osed

learning

disability

IEP;specialedu

catio

ncourses

Une

mployed

Une

mployed

CHD-18*

Est.FSIQ

=101

(at6yrs.6mos)

Diagn

osed

ADHD

Unkno

wn

Dep

artm

entstorewareh

ouse

worker

Une

mployed

CHD-35

Non

eDiagn

osed

learning

disability

IEPgrades

2–12

Odd

jobs

forfamily

mem

bers

Odd

jobs

forfamily

mem

bers

CHD-24†

Non

eDiagn

osed

readingdisorder

andADD

IEPgrades

3–12

Cleaningandmainten

ance

work

Une

mployed

CHD-23†

Non

eNon

eNon

erepo

rted

Food

serviceandjanitorialp

osition

Une

mployed

CHD-17

Non

eNon

eSpecialedu

catio

ncourses

Une

mployed

Une

mployed

CHD-5

Non

eNon

eIEPgrades

9–12

Nursing

assistant

Une

mployed

CHD-30

Est.FSIQ

=75

(at18

yrs)

Diagn

osed

learning

disability;

borderlineADHD

Nospecialaccom

mod

ations;

privatetutorin

gCashier

atfamily

busine

ssUne

mployed

CHD-20

Non

eDiagn

osed

learning

disability

Unkno

wn

Une

mployed

Deceased

CHD-31#

Non

eNon

erepo

rted

Unkno

wn

ITUne

mployed

CHD-33#

Non

eDiagn

osed

learning

disability

andADHD

Non

erepo

rted

Office

supp

ortstaff

Une

mployed

CHD-32#

Non

eDiagn

osed

learning

disability;

ADHD

Specialtutoringin

scho

olpriorto

age7

Une

mployed

Une

mployed

Supe

rscripts

indicate

siblingsets

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 4 of 13

is a developmental disorder, we chose to minimallydemographically correct the T-scores. All T-scores weredemographically corrected for age, while a select fewwere corrected for additional demographic variables asrequired by various scoring software (see Table 3 for fur-ther information). Normative values were obtainedthrough widely used published and commercially avail-able norms derived from generally large and representa-tive samples in the United States. Means and SDs forindividual measures were calculated using data frompatients’ initial neuropsychological evaluations. The subsetof patients who completed reevaluations did so at approxi-mately one-year intervals. Pediatric patients were adminis-tered a measure of general intelligence and parents filledout a self-report form on behavioral and emotional func-tioning (see Appendix for list of all measures).

Additional measuresInformation on the majority of patients’ premorbid func-tioning was obtained through interviews with the patient

and informants. For the three adult patients who re-ported undergoing neuropsychological testing prior toenrolling in the current protocol, results from previoustesting sessions were obtained. Patients underwent com-prehensive neurologic examinations as well, though dis-cussion of such measures is beyond the scope of thepresent manuscript and has been previously reported ona subset of the present cohort [12]. However, here we dopresent data on MRI-based cerebellar and cerebral atro-phy for the full adult cohort that received scans aroundthe time of neuropsychological evaluation (see Table 5).

ResultsPatientsFour pediatric patients (1 male, 3 female; aged 4–5) com-pleted a neuropsychological evaluation. All pediatric patientswere diagnosed with CHD during infancy, and all had re-ceived at least one BMT prior to testing.Fourteen adult patients (10 male, 4 female; aged 17–43)

also completed an initial neuropsychological evaluation,and of those, nine patients (64.29%) had at least one sub-sequent reevaluation. Adult patients were on average 27.3years old (SD = 7.2) at initial evaluation. Age at CHD diag-nosis ranged from birth (n = 7, 50% of total sample) to 43years old. Three patients had previously received a BMT(at 6 months, 3 years, and 10 years of age) and were diag-nosed with classic CHD. One patient was diagnosed withclassic CHD but never received a BMT. The remainingpatients had not received a BMT previously and were di-agnosed with atypical CHD. Many patients had eye or vi-sion conditions such as nystagmus, color vision deficits,myopia, hyperopia, and strabismus. For most of these pa-tients, conditions were mild and treated or corrected andit is not believed that vision problems affected their testresults. A few patients had significant vision problems thatprogressed over subsequent visits. For those patients whohad vision difficulty that could have potentially affectedtest performance, select tests with a vision componentwere omitted from the battery.Many patients also had motor difficulties, such as tremors

and mild upper extremity weakness. However, these difficul-ties would not affect the majority of the administered cogni-tive tests, except those of psychomotor speed andinformation processing. Because tests of psychomotor speedand information processing aim to measure brain-relatedmotor abilities, it would be inappropriate to exclude scoresfrom patients with motor impairments, as these scores definethe neurocognitive phenotype of CHD. Medications taken atthe time of the initial assessment are listed by patient inTable 1. There was only one adult patient who was on Lith-ium and Zoloft for Bipolar Disorder. No other patients had apsychiatric diagnosis (other than a history of a learning dis-order or ADHD) and no one was excluded on the basis ofcomorbid conditions or medication use. Three sets of

Table 2 Table with results for pediatric subsample

n Mean (SD)

General Intelligence

WPPSI-III Verbal IQ 3 47.8 (9.6)

WPPSI-III Performance IQ 4 46.3 (6.8)

WPPSI-III FSIQ 3 45.8 (6.8)

WRAT-4 Word Reading 2 44.0 (10.4)

WRAT-4 Spelling 2 41.0 (1.4)

WRAT-4 Math Computation 2 43.0 (0.5)

Behavioral and Emotional Functioninga

CBCL Emotionally Reactive 3 50.7 (0.6)

CBCL Anxious/Depressed 3 50.3 (0.6)

CBCL Somatic Complaints 3 55.0 (8.7)

CBCL Withdrawn 3 56.3 (9.2)

CBCL Sleep Problems 2 52.0 (4.5)

CBCL Attention Problems 3 57.3 (4.5)

CBCL Aggressive Behavior 3 52.0 (2.7)

CBCL Internalizing Problems 3 50.0 (5.2)

CBCL Externalizing Problems 3 52.0 (5.0)

CBCL Total Problems 3 49.0 (5.0)

CBCL Stress Problems 3 53.0 (2.0)

CBCL Affective Problems 3 51.3 (1.2)

CBCL Anxiety Problems 3 50.3 (0.6)

CBCL Pervasive Developmental Problems 3 55.0 (4.6)

CBCL ADHD Problems 3 54.3 (4.9)

CBCL Oppositional Defiant Problems 3 51.3 (1.2)aHigher scores indicate greater dysfunction

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 5 of 13

siblings participated in the study (two sibling pairs and onesibling trio), while the remaining 7 patients were from inde-pendent families. Additional demographic information canbe found in Table 1.

Neuropsychological findings from the pediatricsubsamplePerformance on the Wechsler Preschool and PrimaryScale of Intelligence-III suggested low, but average abil-ities across individual subtests as well as on the compos-ite measures of Verbal IQ (M = 47.78, SD = 9.65),

Performance IQ (M = 46.8, SD = 6.76), and FSIQ (M =45.78, SD = 6.84). Scores on the Wide Range Achieve-ment Test-4, a measure of academic function, were lowbut within normal limits as well. At time of initial test-ing, no parents indicated any concerns about possibleADHD; however, scores on two scales of attention on aparent-report measure of behavioral and emotional func-tioning (Child Behavior Checklist) indicated slightly ele-vated (though within normal limits) levels of attentionaldifficulties. Other subscales were generally within nor-mal limits (see Table 2).

Table 3 T-scores (M = 50, SD = 10) on formal neuropsychological tests

n Mean (SD) Percent scoring in bottom16th percentile of population

Percent scoring in bottom2.3 percentile of population

General Intelligence

Wechsler FSIQa 12 32.9 (8.1) 67% 42%

WRAT-4 Word Readinga 12 40.1 (8.7) 42% 17%

WRAT-4 Spellinga 8 44.3 (9.5) 38% 13%

WRAT-4 Math Computationa 9 33.2 (6.0) 100% 22%

Executive Function

WCST Total Errorsa 9 30.6 (8.6) 100% 44%

WCST Perseverative Responsesa 9 34.6 (8.8) 56% 22%

Attention/Working Memory

WAIS-III Digit Spana 13 45.9 (7.7) 15% 0%

WAIS-III Letter-Number Sequencinga 10 40.1 (7.0) 40% 0%

CPT-II Omissionsb 9 19.0 (19.5) 78% 78%

CPT-II Commissionsb 9 42.7 (8.4) 22% 11%

CPT-II Reaction Timeb 9 38.3 (9.5) 67% 11%

CPT-II Reaction Time Standard Errorb 9 29.2 (15.6) 78% 56%

Processing Speed

WAIS-III Digit-Symbol Codinga 13 31.5 (6.2) 86% 38%

WAIS-III Symbol Searcha 13 36.9 (5.2) 54% 0%

Language Fluency

COWA FASc 8 36.8 (7.0) 67% 13%

COWA Animalsc 8 35.0 (8.3) 50% 38%

Learning and Memory

NAB Memory Indexa 12 26.4 (12.3) 83% 75%

BVMT-R Learninga 5 23.2 (7.7) 100% 80%

BVMT-R Memorya 5 25.2 (10.1) 80% 80%

HVLT-R Learninga 7 25.1 (8.1) 86% 86%

HVLT-R Memorya 7 28.4 (9.0) 71% 57%

Psychomotor Speed

Grooved Pegboard (dominant)c 8 16.4 (9.3) 100% 100%

Grooved Pegboard (nondominant)c 8 15.4 (9.8) 100% 100%a T-score demographically corrected for age onlyb T-score demographically corrected for age and genderc T-score demographically corrected for age, education, race, and genderFSIQ scores were linearly transformed from standard scores to T-scores based on the normal distribution. T-scores on the CPT-II were scored so that lower T-scorereflect greater inattention (i.e., scoring program-derived output was transformed via the formula 50 - (score-50))

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 6 of 13

Neuropsychological findings from the adult subsampleEarly academic functioningEight adult patients (57.14%) reported having an individ-ualized education program (IEP) or specialized academicaccommodations during school, three (21.43%) did nothave an IEP or specialized academic accommodations,and this data was unavailable for the remaining three pa-tients. Eight patients (57.14%) went on to pursue collegeeducation, although only one of these eight completed aBachelor’s degree. Six patients (42.86%) were previouslydiagnosed with ADHD, of which none were on medica-tion at time of initial testing, though the reasons for notbeing on medication are mostly unknown. Two patientstook medication for ADHD previously, but discontinueddue to side effects (e.g. headaches, vomiting). Seven pa-tients (50%) were previously diagnosed with a learningdisorder. Two of the three patients who had intelligencetesting prior to enrolling in the current protocol had es-timated full-scale IQs (FSIQ; M = 100, SD = 15) in the‘borderline’ range (i.e. between 70 and 79), while onehad an estimated FSIQ of 101. All 14 adult patientscompleted high school, and all but one received a stand-ard high school diploma (as opposed to a special educa-tion diploma).

Intelligence and academic achievementBased on the assessment at NIH, a FSIQ was calculated for12 adult patients. Four patients (28.57%) had an FSIQ be-tween the mean and one SD below, one (7.13%) betweenone and two SD below the population-based mean (bottom16th percentile), and seven (50%) greater than 2 SD belowthe mean (bottom 2.3 percentile; overall M= 32.8, SD= 8.0).Performance on Wide Range Achievement Test-4 subtestswas variable across subjects and across subtests. All adultparticipants that were administered Math Computation (n=9) scored in the bottom 16th percentile (overall M= 33.2,SD= 6.0). Patients appeared to perform better on the WordReading subtest (n= 12), with only five (35.71%) receiving ascore in the bottom 16th percentile (overall M= 40.1, SD=8.7). Similarly, of the eight patients who underwent the Spell-ing subtest, only three received a score in the bottom 16thpercentile (overall M= 44.3, SD= 9.35).

Formal neuropsychological tests of specific domainsTable 3 displays the number of participants, mean T-scores,standard deviations, and percent of participants scoring inthe bottom 16th and bottom 2.3 percentile of the populationfor neuropsychological tests that were administered to atleast five participants. Overall, on average participants

Table 4 T-scores (M = 50, SD = 10) on performance and rating scales

Baselinen

BaselineMean (SD)

Baseline + Follow-upn

Baseline + Follow-upMean (SD)

Behavioral and Emotional Functioninga

FrSBe Family Before Apathy 9 63.6 (21.4) 12 68.0 (20.1)

FrSBe Family Before Disinhibition 9 46.2 (11.0) 12 50.2 (17.4)

FrSBe Family Before Executive Dysfunction 9 59.9 (17.1) 12 64.0 (16.5)

FrSBe Family Before Total 9 50.2 (22.4) 12 56.8 (23.1)

FrSBe Family After Apathy 9 73.4 (29.3) 12 75.6 (25.4)

FrSBe Family After Disinhibition 9 49.2 (14.3) 12 52.6 (19.0)

FrSBe Family After Executive Dysfunction 9 62.1 (19.8) 12 66.4 (19.2)

FrSBe Family After Total 9 62.3 (21.2) 12 66.3 (20.6)

FrSBe Self Before Apathy 7 54.3 (11.2) 10 54.0 (9.5)

FrSBe Self Before Disinhibition 7 43.1 (12.3) 10 46.0 (11.5)

FrSBe Self Before Executive Dysfunction 7 51.3 (14.8) 10 52.6 (14.8)

FrSBe Self Before Total 7 49.7 (15.8) 10 51.4 (13.3)

FrSBe Self After Apathy 7 57.1 (18.5) 11 54.7 (16.4)

FrSBe Self After Disinhibition 7 41.7 (10.9) 11 45.2 (10.6)

FrSBe Self After Executive Dysfunction 7 50.9 (16.5) 11 49.7 (16.9)

FrSBe Self After Total 7 49.9 (18.3) 11 49.5 (17.3)

Mooda,b

Beck Depression Inventory – II 10 6.4 (6.1) 12 6.6 (6.4)

Beck Anxiety Inventory 6 3.2 (2.6) 11 4.8 (3.7)a Higher scores indicate greater dysfunctionb Raw total score out of 63Baseline = data gathered from first visits only; Baseline + Follow-up = data gathered from first or subsequent visits

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 7 of 13

performed below average on all measures with the exceptionof Wechsler Adult Intelligence Scale-III Digit Span. Thegreatest impairments were observed on the Grooved Peg-board, a test of psychomotor speed, where all participantsscored in the bottom 2.3 percentile. Participants also per-formed significantly below average on measures of learningand memory and attention. Overall NP (neuropsychological)performance was not significantly associated with participantage (β=− 0.1, t(13) =− 0.30, p= 0.75), suggesting that differ-ences in NP performance observed across participants wasnot influenced by differences in participant age.In addition to being examined using formal neuropsycho-

logical tests, executive function was further examined usingFrontal Systems Behavior Scale (FrSBE) informant (n = 9)and self-reports (n = 7; see Table 4). Scores on theinformant-report apathy (M= 73.4, SD = 29.3) and execu-tive dysfunction (M= 62.1, SD = 19.8) subscales were ele-vated (with elevated scores indicative of impairment) forsix and four patients, respectively; elevated scores on thedisinhibition subscale were only observed in two patients(M = 49.2, SD = 14.3). Incorporating those who had in-formant (n = 12) or self-report (n = 11) data collected at alater evaluation, scores on informant-report apathy (M=68.0, SD = 20.1) and executive dysfunction (M= 64.0, SD= 16.5) subscales were elevated for nine and seven pa-tients, respectively; elevated scores on the disinhibitionsubscale were observed in four patients (M= 52.6, SD =19.0). The mean overall informant FrSBe score wasslightly elevated at 62.3 (SD = 21.2), and more elevatedwith inclusive data (M = 66.3, SD = 20.6). Comparing in-formant (M= 63.55, SD = 19.11) versus self-report scores

(M = 49.45; SD = 17.31) on the subscales, informants re-ported significantly greater impairment than patients;t(10) = 2.33, p = .042, d = .70 (see Fig. 1). Data collected atbaseline and at follow-up evaluations was used for thiscomparison in order to maximize sample size; however,this finding should be interpreted with caution due to thevery small sample (n = 11).

MoodMood was evaluated using the self-report, 21-item BeckDepression Inventory-II (BDI-II; n = 10) and Beck Anx-iety Inventory (BAI; n = 6; see Table 4). Depression (M =6.4, SD = 6.1) and anxiety scores (M = 3.2; SD = 2.6) wereboth in the minimal range (0–13; 0–7) at the first evalu-ation, and when incorporating those who had data col-lected at a later evaluation (BDI-II: n = 12; M = 6.6, SD =6.4; BAI: n = 11; M = 4.8; SD = 3.7). Across follow-upevaluations, depression symptoms remained in the min-imal range (0–13), and anxiety symptoms were in theminimal (0–7) to mild range (8–15).

Longitudinal cognitive functioningOf the 14 patients, nine had repeated evaluations for the pur-poses of this study with the average number of follow-upevaluations being 2.86 (SD= 1.79, range = 2–6), with evalua-tions conducted approximately 1 year apart. Data from pa-tients’ first administration of a particular test was comparedto that from their last administration to elucidate whetherpatients evidenced a decline in functioning over the time oftheir participation in the study. We report results on thetests for which at least six patients had longitudinal data. Of

Table 5 Adult patient clinical neuroimaging findings and average T-scores

Neuroimaging

Patient ID Cerebellar Atrophya Cerebral Atrophy Average neuropsychological T-score(M = 50, SD = 10)

CHD-17 0 0 43

CHD-27 + 0 31

CHD-26 + 0 27

CHD-19 + 0 40

CHD-24 0 + 32

CHD-5 Not scanned Not scanned 38

CHD-23 + ++ 35

CHD-20 ++ +++ 30

CHD-30 +++ +++ 30

CHD-33 0 + 32

CHD-31 0 + 43

CHD-18 + 0 42

CHD-32 ++ +++ 30

CHD-35 0^ 0^ 30aNeuroimaging revealed that all individuals had cerebellar hypoplasia0 = no abnormality, + =mild impairment, ++ =moderate impairment, +++ = severe impairment, ^=based on non-NIH scan

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 8 of 13

the 25 variables examined, three exhibited changes over time.Wechsler Adult Intelligence Scale-III arithmetic scores ex-hibited improvements between first and last administration(t(5) = 3.80, p= 0.01), while Conners’ Continuous Perform-ance Test-II omissions and commissions exhibited declines(t(7) = 2.63, p= 0.03 and t(7) = 3.78, p < 0.01, respectively).Patients’ average NP T-scores did not decline across evalua-tions (t(8) = 0.07, p= 0.94; see Fig. 2).

Transplant, diagnosis and cognitive functioningExploratory analyses were conducted to detect potentialdifferences between adult patients with a diagnosis ofclassic CHD and previous BMT (n = 3) and with a diag-nosis of atypical CHD and no previous BMT (n = 10). Asthere was only one adult patient with a diagnosis of clas-sic CHD that did not receive a BMT, this patient was ex-cluded from analyses. Average NP T-scores in patientswith classic CHD and previous BMT (M = 30.27,SD = 0.90) were significantly lower than those of patients

with atypical CHD and no previous BMT (M = 35.77,SD = 5.95; t(11) = 2.95, p = 0.01). Additionally, T-scoreson the Wide Range Achievement Test-4 Spelling subtestwere 14 points higher in patients without BMTs (t(7) =3.04, p = 0.03), T-scores on the Wide Range Achieve-ment Test-4 Spelling Math Computation subtest were10.5 points higher (t(8) = 3.81, p = 0.04), and T-scores onthe Wechsler Adult Intelligence Scale-III Block Designsubtest were 11 points higher (t(7) = 2.46, p = 0.04). Noother significant differences were detected between thetwo groups on any individual measure.

DiscussionIncreased survival rates due to early BMTs, as well asthe identification of individuals with milder forms of thedisorder, have afforded the ability to study the manifesta-tions of CHD in adulthood, and their longitudinal pro-gression. The present study represents the first to useformal neuropsychological tests to evaluate the cognitive

Patient ID Number of evaluations

Years between first and last evaluation

Average number of years between

evaluationsDifference

CHD-26 3 4 1.96 - 2.2CHD-19 5 5 1.26 - 1.2CHD-24 4 4 1.32 - 0.5CHD-5 6 6 1.22 + 4.1CHD-23 4 4 1.32 + 3.1CHD-30 4 4 1.33 - 3.2CHD-31 2 1 1.07 - 1.7CHD-18 5 5 1.26 - 0.1CHD-32 2 1 1.07 - 2.2

Fig. 2 Changes in average T-scores between initial and final visits for adult patients who completed more than one evaluation. Note that all T-scores are not based on the same battery of test for all patients

Fig. 1 Differences in T-scores between self-reported and informant-reported behaviors related to executive function. Higher scores indicategreater dysfunction. Three patients were excluded due to incomplete data. There was a significant difference between self-reported behaviors (M= 49.45; SD = 17.31) and informant-reported (M = 63.55, SD = 19.11); t(10) = 2.33, p = .042, d = .70

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 9 of 13

phenotype of CHD. Results from pediatric patients (all ofwhom previously received BMTs) suggest a lack of impair-ments in cognition and emotional functioning. Resultsfrom adult patients (the majority of whom did not previ-ously receive BMTs), on the other hand, suggest impair-ments across almost all cognitive domains measured,longitudinal stability of such impairments across the studyperiod, and a potential influence of diagnosis (i.e., classicversus atypical CHD) or prior BMT on cognition.Though results from formal neuropsychological testing

during childhood were not available for the majority of adultpatients, reports of adult patients’ educational history aregenerally suggestive of early neuropsychological impair-ments. More than 75% of patients were diagnosed with alearning disability, ADHD, or both as a child; in contrast,about 8 % of children in the US population are diagnosedwith a learning disability, and about 5 % are diagnosed withADHD [27]. Interestingly, data from the pediatric sample inthe present study does not support the notion of increasedneuropsychological impairment in pediatric CHD patients,though it may be that such impairments are not readily ap-parent until later on in formal schooling. On the other hand,early identification, intervention, and BMT may protectagainst the presumed deleterious effects of CHD and its con-comitant immunological complications on cognition. Thatall pediatric patients received at least one BMT in infancy ascompared to just three of adult patients may contribute tothe discrepancies observed in childhood neuropsychologicalfunction. Interestingly, the seemingly protective effect ofBMT in pediatric patients was not observed in adult patients,as patients with classic CHD and prior BMTs exhibited sig-nificant neuropsychological impairments. It is possible thatwhen adult patients received BMTs, there was significantlygreater neurotoxicity in the chemotherapy preparative proce-dures, whereas this neurotoxicity has been reduced and isnot experienced in patients receiving BMTs more recently.The greatest and most consistent impairments observed in

adult patients were in psychomotor speed, where mean scoresfor both dominant and nondominant hands fell in the bottom0.1 percentile. The frank psychomotor impairments describedhere are concordant with previously reported motor impair-ments in CHD such as Parkinsonism [6, 10–12] and dysme-tria [12], as well as with cerebellar atrophy, cerebellarhypoplasia, and cerebral atrophy noted in subsets of CHD pa-tients [12; see also Table 5]. Abnormalities have been moreconsistently reported in the posterior fossa of CHD patients[12], which may also modulate psychomotor function. Neuro-psychological tests of other cognitive functions may also relyon psychomotor functioning to a limited degree and couldtherefore also be somewhat affected. Although our limitedsample size makes it difficult for us to draw any firm quantita-tive conclusions regarding cognition-to-neuroimaging correla-tions, the data presented in Table 5 suggests that individualswith the greatest degree of cerebellar and cerebral atrophy

have a trend toward greater neurocognitive impairment basedon their average T-score.In the present study, two measures of information pro-

cessing speed (Wechsler Adult Intelligence Scale-IIIDigit Symbol Coding and Symbol Search) as well as twomeasures of attention (Conners’ Continuous Perform-ance Test-II RT and RT Standard Error) requiring motoroutput were administered. Scores on these tests may bedepressed due to psychomotor impairments, potentiallyobscuring true functional abilities in attention and infor-mation processing speed. However, scores relatively in-dependent of psychomotor demands were also belowaverage. Second to that of psychomotor function, thegreatest difficulties were observed in tests of learningand memory, with both visual memory (assessed usingthe Neuropsychological Assessment Battery and BriefVisuospatial Memory Test-Revised) and verbal memory(assessed using the Neuropsychological Assessment Bat-tery and Hopkins Verbal Learning Test-Revised) exhibit-ing similar levels of impairment, with mean scores in thebottom 2.3 percentile. Future work should examineneuropsychological and neuroimaging data in concert toelucidate the anatomical basis of the cognitive profile ofCHD observed in the present study.Progressive cognitive decline was not observed in the

present study. While it may be that the trajectory of cogni-tive decline in CHD patients is similar to that of controls,it is also possible that these trajectories differ, but that thepresent study was not able to detect these differences.It is possible that CHD patients do in fact experience cog-

nitive decline, but that it occurs over a course of a time spangreater than that of the present study; for example, patientsmay experience a period of unchanging cognitive function,followed by a rapid decline. It also may be that CHD patientsexperience an ‘accelerated aging’ process such as that pro-posed in HIV patients [24], where cognitive decline is experi-enced more rapidly and at an earlier age as compared tohealthy controls. As all but one patient in the present samplewere younger than 40, we were unable to examine cognitionat ages where decline would be expected. The mild level ofneuropsychological impairment detected among pediatricCHD patients relative to that observed in adult patients maymirror general neurologic involvement in CHD, whereinsubtle abnormalities are noted in childhood, but are followedby a period of progressive degeneration in early adulthood,wherein abnormalities and impairments become increasinglypronounced. Alternatively, it is possible that CHD involvesan early curtailing of mental development or plateauing, asopposed to loss of functioning.Although other chronic multisystemic diseases may also

involve progressive degeneration in neurologic function andin some cases in cognitive function, the proposed two-stagemodel here may be unique to CHD. Our data suggest subtleand mild deficits in childhood, followed by progressive

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 10 of 13

neurological and cognitive decline in adulthood, which is apattern atypically observed in other chronic multisystemicdiseases. It is important to note, however, that in absence oflongitudinal data following CHD patients from childhoodinto adulthood, we cannot be certain about the exact patternof neuropsychological decline in this clinical population. Itshould also be pointed out that the extent and pattern of def-icits observed in adult CHD patients --that of disproportion-ate and severe psychomotor and memory difficulties -- whilenot completely unique to CHD, as it is found in other condi-tions such as Parkinson’s Disease and subcortical dementias,is not found in many other multisystemic diseases.Our finding of low neuropsychological function in

all adult patients serves as a cautionary note for doc-tors, family members, and others involved in the careof CHD patients. However, the present study may beviewed somewhat positively insofar as there was nosignificant developmental deficits in our transplantedpediatric patients nor evidence of rapid decline in ouradult sample. Patients with CHD in high school mayexperience greater difficulty in school than their un-affected counterparts, but it is possible for patients tocomplete high school when provided with special ac-commodations, and even when not provided withsuch accommodations. Greater difficulties may be ex-perienced during the pursuit of postsecondary educa-tion, where academic support may not be as readilyavailable. Several patients were able to find employ-ment despite neuropsychological impairments and alack of postsecondary education, but the majority ofpatients who were employed at their first evaluationwere no longer employed at their last. Though thiswould potentially suggest a worsening of cognitionover time, no longitudinal decreases in cognition wereobserved. It is possible that the trend of previouslyemployed patients being unemployed at follow up canbe explained by a progression of the physical featuresof CHD, rather than by cognitive features, though theextent to which physical and cognitive symptomsuniquely contribute to impairments in functioning aredifficult to estimate. It is also positive, and perhapsunexpected, that despite their impairments in cogni-tion and in everyday functioning, CHD patients reportminimal amounts of depression and anxiety. ThoughFrSBe subscale scores indicate an elevated level ofself-reported apathy, which is typically a core featureof depression, this heightened apathy does not mani-fest in elevated depression scores. As indicated bylow executive functioning across traditional neuro-psychological tests and the FrSBe, as well as by dis-crepant FrSBe scores in patients and informants,self-awareness among CHD patients may be low, andit may be this low self-awareness that in part explainslow levels of reported depression and anxiety.

The present study was not without limitations. First,that the majority (11/14) of adult patients in thepresent study did not have BMTs suggests most ofour patients may have had a milder or simply uniquevariant of CHD, and that their results may thereforenot generalize well to the broader population of CHDpatients who typically require BMTs for survival. Sec-ond, the fact that not all patients received the sametesting battery contributes to the low number of pa-tients having completed any one particular test. Third,because the adult patients with classic CHD receivedBMTs and no patients with atypical CHD receivedBMTs, we are unable to disentangle the unique effectsof BMT and CHD diagnosis (i.e. classic versus atyp-ical) on cognition. Despite these limitations, thepresent study represents the first attempt at formallytesting multiple cognitive domains in the CHD popu-lation, whereas prior research on neuropsychologicalfunction in CHD has been largely derived from casereports and informal measures of cognition.Our results suggest several avenues for future work.

First, longitudinal studies beginning in childhood andcontinuing into adulthood should be employed to betterelucidate the trajectory of neuropsychological functionin CHD patients. Such studies involving deep phenotyp-ing would afford the ability to examine possible mecha-nisms contributing to cognitive impairment in CHD asthe mechanisms by which mutations in the LYST gene inCHD deleteriously affect cognition and CNS functionmore generally have not yet been identified. Longitudinalstudies would also allow physicians and caregivers to in-vestigate the best academic resources and/or medica-tions to provide to a patient group with a highprevalence of ADHD and learning disabilities. Finally,prospective pre- and post-BMT studies should be con-ducted to evaluate the effect of BMT on cognition inCHD patients, as some prior work has suggested a dele-terious effect of BMT [25, 26]. As the majority of CHDpatients require BMT for survival past childhood andadolescence, the ability to accurately identify the risks ofBMT may significantly impact the post-BMT care andservices patients receive.

ConclusionAdults with CHD exhibit cognitive impairment across awide range of neuropsychological domains, and theseimpairments may be compounded in patients with clas-sic CHD who previously received BMTs. Longitudinalanalyses suggest that there is little evidence of cognitivedecline in adult CHD patients over a period of severalyears. Pediatric CHD patients with prior BMTs per-formed within the average range, but long-termfollow-up analyses are required to elucidate the trajec-tory of cognition in CHD.

Shirazi et al. Orphanet Journal of Rare Diseases (2019) 14:101 Page 11 of 13

AbbreviationsBMT: Bone marrow transplant; CHD: Chediak-Higashi Disease; FSIQ: full-scaleIQ; HLH: hemophagocytic lymphohistiocytosis; IEP: individualized educationprogram; NIH: National Institutes of Health; NP: neuropsychological;SD: standard deviation

AcknowledgementsThe authors thank the patients and families who participated in this work.

FundingThis research was supported by the Intramural Research Programs of theNHGRI (ZIDHG200352) and NIMH (ZIAMH002922).

Availability of data and materialsThe datasets used for the present analyses can be made available by thecorresponding author (JS) upon request.

Authors’ contributionsJS, EAW, CT, and WJI conceived the study and test procedures. TS, JS, GBR,EAW, and ACS administered and scored the neuropsychological battery. TS,JS, LH, and ACS participated in the analysis and interpretation of results. TS,JS, LH, and GBR wrote the manuscript, with all authors reading andapproving the final manuscript.

Ethics approval and consent to participateThe present study was approved by the National Human Genome ResearchInstitute IRB. Informed consent was obtained from either patients themselvesor their legal guardians prior to study participation.

Consent for publicationNot applicable.

Competing interestsAll authors declare they have no competing interests to disclose. Theopinions expressed in the article are the views of the authors and do notreflect the views of the Department of Health and Human Services or theUnited States government.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1National Institute of Mental Health, 10 Center Drive, MSC 1274, Bethesda,MD 20892, USA. 2National Human Genome Research Institute, Bethesda, MD,USA.

Received: 3 August 2018 Accepted: 19 March 2019

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AppendixTable 6 Assessment battery

Domain Assessment

FSIQ WASI

WAIS-III

WPPSI-III (pediatric sample only)

Information Processing Digit-Symbol Coding (WAIS-III)

Symbol Search (WAIS-III)

Attention Digit Span (WAIS-III)

Conners’ Continuous PerformanceTask-II (CPT-II)

-Omissions

-Commissions

-Reaction time

-Reaction time standard error

Language Fluency Controlled Oral Word Association Task(COWA) - FAS

Controlled Oral Work Association Task(COWA) - Animals

Boston Naming Test

Learning and Memory Neuropsychological Assessment Battery(NAB) Memory Module

Hopkins Verbal Learning Test (HVLT-R)

-Total recall

-Delayed

Brief Visuospatial Memory Test (BVMT-R)

-Total recall

-Delayed

Psychomotor Speed Grooved Pegboard (Dominant Hand)

Grooved Pegboard (Nondominant Hand)

Executive Functioning Wisconsin Card Sorting Task (WCST)

-Errors

-Perseverative responses

Frontal Systems Behavior Scale (FrSBe)

-Total (informant report)

-Total (self-report)

Emotional and BehavioralFunctioning

Child Behavior Checklist (CBCL; pediatricsample only)

Not all patients were administered all the above tests. However, on their first visits,all patients were administered at least one assessment of information processing,attention, learning and memory, and subtest from the WASI/WAIS. Additionally ontheir first visits, all patients but one were administered at least one test ofexecutive functioning, psychomotor speed, and language fluency. Patients withfollow-up evaluations were administered similar batteries across evaluations

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